Identification of structurally novel inhibitors of lysine methyltransferase G9a has been a subject of intense research in cancer epigenetics. Starting with the high-throughput screening (HTS) hit - obtained from the chemical library of the University of Tokyo Drug Discovery Initiative, the structure-activity relationship of the unique substrate-competitive inhibitors was established with the help of X-ray crystallography and fragment molecular orbital (FMO) calculations for the ligand-protein interaction. Further optimization of the characteristics and drug metabolism and pharmacokinetics (DMPK) properties led to the identification of (RK-701), which is a structurally distinct potent inhibitor of G9a/GLP (IC = 27/53 nM). Compound exhibited remarkable selectivity against other related methyltransferases, dose-dependent attenuation of cellular H3K9me2 levels, and tumor growth inhibition in MOLT-4 cells . Moreover, compound showed inhibition of tumor initiation and growth in a carcinogen-induced hepatocellular carcinoma (HCC) mouse model without overt acute toxicity.
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